Children born with sickle cell anemia (SCA), caused by a genetic defect in hemoglobin, have severe anemia and damage to virtually all the body organs: the damage begins in infancy, and is frequently fatal by early adulthood. This is one of the most common inherited diseases in the world: because of California’s ethnic diversity it is relatively common here, often in underserved populations. Our research team is dedicated to the treatment and, when possible, cure of this devastating disease. We and others have shown that transplantation of blood stem cells from bone marrow can cure SCA, and this type of stem cell therapy also is used in treating other blood and genetic diseases. Unfortunately, not all individuals are cured after bone marrow transplantation, as this is a risky treatment. We have carried out pioneering work showing that blood from the umbilical cord (“cord blood”) of a newborn sibling can be used to cure blood disease in the affected sibling. A significant part of our effort is devoted to discovering ways to improve and extend the use of cord blood for blood cell transplantation and make this treatment less risky. Most recently, we have found that the placenta itself is a rich source of blood stem cells, and possibly also of stem cells for tissues other than blood. We have developed a program of clinical research that is closely associated and integrated with lab research that supports investigations into ways to improve stem cell transplantation and make it available to more people.
We propose to use support from CIRM to organize a planning group of scientists who conduct clinical and preclinical research to focus on new methods to improve blood stem cell transplantation for SCA. This investigative team will plan therapies using stem cell sources that include umbilical cord blood, placenta, bone marrow and embryonic stem cells. We will conduct a clinical trial to determine if it is safe and effective to perform transplantation with purified hematopoietic stem cells. We will explore new methods to increase yields of cord blood stem cells after collection, so that cord blood transplantation can be made available to a broader population of recipients. We will also investigate and develop the use of placentally derived blood stem cells in transplantation, which may in the next few years extend this type of therapy to many more individuals who currently need it but do not have suitable stem cells available. We will also investigate treatments that will take longer to develop, including research that will study if it is possible to expand and then purify a population of immune cells from embryonic stem cells, and eventually improve the safety of unrelated and mismatched donor transplantation. This planning group is devoted to extending the use of blood stem cell transplantation for genetic diseases in California, and is very likely to contribute significantly to CIRM’s goal of providing new cures for human disease.

Statement of Benefit to California:

The inherited blood disease sickle cell anemia afflict significant numbers of individuals in California, particularly in underserved populations; affected individuals require expensive treatment, and experience severe tissue damage that degrades quality of life and is often fatal. Individuals afflicted by sickle cell anemia can be cured by transplantation of blood stem cells. Nevertheless the application of this treatment is limited because the supply of donated bone marrow stem cells is limited, and because it is necessary to match certain characteristics of the donor’s and host’s immune systems. In order to expand the application of transplantation for sickle cell anemia, we will assemble a team of clinical and basic scientists from California biomedical institutions with the goal of developing and conducting clinical trials of novel stem cell therapies for sickle cell anemia. We will use support of the planning group to formulate a feasible path to carry out research dedicated to the improvement of methods that use stem cells from cord blood, placenta, bone marrow and embryonic stem cells for blood stem cell transplantation. The purpose of this planning group is to develop a final application that will develop collaboration and methods that directly support the proposed transplantation studies, with the aim that these may produce advances that will allow many more people to receive this curative therapy. In the course of this research, individuals with inherited blood diseases will receive transplants, and our extensive experience indicates these will be curative in the large majority of cases. The enhanced and extended lives of these individuals will represent a direct benefit; the savings to the health care system as a consequence of their cure is less direct but will benefit all California taxpayers. Ultimately the knowledge and experience produced by the research will contribute to the goal of making blood stem cell transplantation available to a much broader group of patients, thus greatly extending the benefits to the affected individuals and to the taxpayers of California.

Review Summary:

Executive Summary
The applicant proposes to organize a team of basic and clinical scientists to develop a stem cell-based approach for the treatment and cure for sickle cell anemia (SCA). SCA is a hereditary hemoglobin disorder which affects a disproportionate number of children in California because of the state’s ethnic diversity. The PI proposes to address several of the current barriers to the success and adoption of allogeneic hematopoietic stem cell (HSC) transplantation as curative therapy for patients with SCA. Most of these patients are Asian, African or African American and have increased difficulties identifying unrelated donors in international registries due to low representation of these ethnic groups in registries. Thus, strategies to overcome histocompatibility barriers are particularly important in this patient population, as noted in this application. Furthermore, while SCA is a debilitating disease leading to significant health problems and premature deaths in adults, the fact that it is not immediately fatal in childhood provides an imperative to find ways to lessen the toxicity associated with current myeloablative chemotherapy regimens which are now necessary to promote engraftment of donor cells. Enthusiasm for early transplant in patients with SCA, the approach with the best long term outcomes, will increase if toxicity can be limited, and if graft versus host disease (GVHD) can be controlled without compromising engraftment.
The PI plans to develop several approaches with the goal of having a clinical trial underway within five years. One of the approaches includes purification of hematopoietic stem cells to prevent GVHD. The associated problems of engraftment, graft failure and delayed immune reconstitution will be addressed by increasing the number of HSCs and optimizing the pretransplantation conditioning regimen. A proof of concept study for this approach is currently underway as a collaboration with a biotech firm in California. Another approach to be addressed by the investigators is the use of umbilical cord blood cells as a source of HSC for transplantation. Umbilical cord transplantation is associated with lower GVHD rates than adult cell transplantation from donors with similar histoincompatibilities. The investigator has established a sibling donor cord blood program for directed donation of cord blood in patients with sickle cell anemia or thalassemia. Preliminary data using this approach are quite encouraging, with relatively low graft rejection rates, a low incidence of chronic GVHD and some acute GVHD. In another approach, the PI proposes to study the addition of cells from human placenta, which is a rich source of HSC’s and other progenitor populations that might have regenerative activity for organs damaged by sickle cell disease. In the final approach, the PI proposes to use a chemical treatment approach to reduce GVHD-inducing potential of T-cells while preserving their ability to promote engraftment. Overall the approaches discussed in the proposal address the current barriers in allogeneic HSCT in SCA and are likely to lead to strategies that will be applied in the clinic within the next 5 years.
There was a general agreement among the reviewers that this is a well thought-out proposal. The PI has assembled a good team of experts from academic institutions and industry to address the current barriers to allogeneic transplantation for a clinically very important area of hereditary disease with no available curative treatment. Reviewers thought the allogeneic HSC transplantation approaches described in the proposal were feasible. Some concerns were raised regarding the lack of information provided in the application on the industrial collaboration for the purification of HSCs for transplantation; such approaches in the past have not always been successful. Regarding the use of umbical cord blood stem cells to reduce GVHD, panelists questioned whether there will be enough cells. The reviewers agreed that the addition of cells from human placenta was the most interesting and innovative aspect of the proposal; however, this concept is new and has not been investigated in any depth in animal models.
The PI is an international expert in hematopoietic stem cell transplantation for sickle cell anemia, He/she has previously served as the PI on a sponsored clinical trial studying the role of allogeneic transplantation from matched related donors in SCA. He/she has also conducted a trial of umbilical cord blood transplantation in patients with SCA and thalassemia major. Reviewers concurred that he/she is well suited to carry out both the planning process and to lead the research team that will conduct this work. Reviewers agree that the planning phase is adequate and could lead to a competitive application for a subsequent disease team research award.
Reviewer Synopsis
The focus of this proposal is extend the work of the PI and associated investigators in overcoming the barriers to the use of allogeneic hematopoietic stem cell transplantation (HSCT) to cure patients with sickle cell anemia. These investigators have a demonstrated track record in the use of HSCT demonstrating that it can provide curative therapy, particularly in patients with a good performance status. However, concerns about transplant related morbidity and mortality, late effects, graft versus host disease and rejection have limited enthusiasm for the approach. The PI proposes to develop a team to address many of these obstacles in the setting of human clinical trials over the next 5 years. The work is feasible, timely and important. Collaborations with investigators in industry and academia broaden the strength and scope of the team and proposed projects.
Reviewer One Comments
Concept:
Sickle Disease is a major problem, affecting one in every 375 African Americans and 6,000 individuals in California. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only know cure for this disease. However, only about 20 percent of individuals have a suitable HLA identical donor, only children in relatively in good condition are considered for this therapy, and there is significant mobility and mortality associated with HSCT. The Principal Investigator proposes strategies to improve the efficacy and safety of allogeneic HSCT for the treatment of this disease. He plans to develop several approaches with the goal of having a clinical trial underway within five years of beginning the award. The strategies include purification of hematopoietic stem cells to prevent GVHD. The associated problems of engraftment, graft failure and delayed immune reconstitution will be addressed by increasing the number of HSC’s and optimizing the pretransplantation conditioning regimen. A clinical trial to test this approach is already underway involving the PI and Dr. Irving Weissman in collaboration with a company, Cellerant Inc. However, details are not provided about the approach. A similar concept (high dose HSCT with increased recipient cytoablation) has been evaluated in the context of hematologic malignancy in Italy and elsewhere. While GVHD has been successfully avoided in patients receiving very high intensity conditioning and high doses of enriched haploidentical hematopoietic stem cells, high infectious complication rates due to slow immune reconstitution has been a major limitation. Moreover, the high intensity conditioning regimen is unlikely to be tolerated by adult sickle cell disease patients who have significant end organ damage. Thus, this concept may be somewhat premature as a way of overcoming the existing limitations to HLA-mismatched HSCT in sickle cell disease. Another approach to be addressed by the investigators is the use of umbilical cord cells as a source of HSC for transplantation. Umbilical cord transplantation is associated with lower GVHD rates than adult cell transplantation from donors with similar histoincompatibilities. The investigator has established a sibling donor cord blood program for directed donation of cord blood in patients with sickle cell anemia or thalassemia. Preliminary data using this approach are quite encouraging, with relatively low graft rejection rates, a low incidence of chronic GVHD and some acute GVHD. The investigator also proposes to study the addition of cells from human placenta, which is a rich source of HSC’s and other progenitor populations that might have regenerative activity for organs damaged by sickle cell disease. While it is the most interesting and innovative aspect of this proposal, this concept is relatively new and has not been investigated in any depth in animal models. Finally, the investigators propose to explore the use of synthetic psoralen with exposure to ultraviolet light to reduce the GVHD-inducing potential of T-cells in the hope of preserving their ability to promote engraftment. This is a mature concept that seems ready for clinical trial in this setting.
Principal Investigator:
Dr. Walters is an international expert in hematopoietic stem cell transplantation for sickle cell anemia, having led the first multi-center NIH-supported clinical investigation in the 1990’s that included enrollment from 27 centers. He recently led another multi-center trial of UCB transplantation for sickle cell disease and thalassemia. Thus, he has strong experience leading multi-center clinical trails in sickle cell disease. He has a close relationship with the Center for International Blood and Marrow Transplantation (CIBMTR) that fosters collaboration in clinical trials. Dr. Walters is co-chair of the Non-Malignant Diseases Working Group of the CIBMTR and is therefore uniquely positioned to coordinate multi-center collaborative efforts. The comprehensive sickle cell center in Oakland is one of eight clinical centers of the Sickle Cell Disease Clinical Research Network, for which Dr. Walters serves as PI. In collaboration with the Pediatric Blood and Marrow Transplantation Consortium, Dr. Walters has led efforts to foster collaboration between these networks and conduct a trial of unrelated donor transplantation for sickle cell disease. The study will be conducted with support by the NHLBI and NCI in partnership with the Sickle Cell Disease Clinical Research Network, the NMDP and the BMT Clinical Trails network. Dr. Walters has also formed a collaboration with ViaCell, which is a commercial entity that stores cord bloods for directed donation. The disease team will collaborate with ViaCell to develop a placental cell therapy. Thus, the PI is well-positioned to lead the Disease Team Award application.
Planning Approach:
A team has been assembled that includes an advisory committee (Drs. Weissman, Vichinsky, Treadwell, Lubin and Gluckman) to advise Dr. Walters. Dr. Harvath will serve as a consultant on the regulatory issues associated with placental storage. The remainder of the group is divided into a basic team (Drs. Robey, Winoto, Weissman), a preclinical research team (Drs. Kuypers, Walters, ViaCell) and a clinical research team (Drs. Walters, Vichinsky, Cellerant, Inc.), Biostatistics consultants and the sickle cell Community Advisory Council will advise the clinical research group. A day-long introductory workshop will be conducted with presentations from all groups and will be attended by the advisory committee, FDA consultants and the Sickle Cell Advisory Council members. The goal of the workshop will be to begin to formulate a response to the potential pitfalls in the clinical translation of each project and begin defining development. After three monthly group meetings, a half-day workshop will be held to update the group on the progress and to select projects for the final disease award application. The final three months will be spent in preparing an application. This is a reasonably detailed and well thought-out proposal.
Reviewer Two Comments
Concept:
The PI proposes to address several of the current barriers to the success and adoption of HSCT as curative therapy for patients with sickle cell anemia. He has brought together a team of experts from academia and industry to participate in the planning phase of research effort. With experts in HLA, immune tolerance, stem cell isolation and propagation, umbilical cord blood banking and data support through the CIBMTR, he has all of the pieces in place to plan the next steps in what will be a several decade endeavor to optimize this therapy for patients with sickle cell disease. This is highly relevant and important because HSCT is the only current cure for this disease which affects >350,000 new births annually around the globe. Most of these patients are Asian, African or African American and have increased difficulties identifying unrelated donors in international registries. Thus, strategies to overcome histocompatibility barriers are particularly important in this patient population, as noted in this application. Furthermore, while SCA is a debilitating disease leading to significant health problems and premature deaths in adults, the fact that it is not immediately fatal in childhood provides an imperative to find ways to lessen the toxicity associated with current myeloablative chemotherapy regimens which are now necessary to promote engraftment of donor cells. Enthusiasm for early transplant in patients with SCA, the approach with the best long term outcomes, will increase if toxicity can be limited, GVHD can be controlled without compromising engraftment. The approaches discussed in this application address these issues and are likely to lead to strategies that will be applied in the clinic within the next 5 years.
Principal Investigator:
Dr. Mark Walters is an established investigator in the area of HSCT for Sickle Cell Anemia. He has previously served as the PI on an NHLBI sponsored clinical trial studying the role of allogeneic transplantation from matched related donors in SSA. He is recognized as an international expert in this field. Dr. Walters has also conducted a trial of umbilical cord blood transplantation in patients with SSA and thalassemia major. He is well suited to carry out both the planning process and to lead the research team that will conduct this work.
Planning Approach:
The planning phase is adequate and likely to lead to a competitive application for subsequent disease team research awards.